• Interactions between dynorphin A-(1--13) and morphine: In vivo effects on EEG, in vitro effects on tritium-morphine binding, and correlations between them in naive and morphine tolerant rats

      Meng, Yuqing; Young, Gerald A. (1993)
      Utilizing an in vivo EEG functional assay and in vitro receptor binding techniques, the mechanisms of the modulatory effects of dynorphin A-(1-13) on morphine-induced EEG effects and receptor binding in naive vs. morphine-tolerant rats were studied. In naive rats, dynorphin A-(1-13) i.c.v. pretreatment significantly attenuated cumulative i.v. morphine-induced EEG spectral power and the maximal response, although dynorphin A-(1-13) alone produced little or no EEG bursting activity. Dynorphin A-(1-13) also significantly decreased the maximal binding (B{dollar}\sb{lcub}\rm max{rcub}{dollar}) for ({dollar}\sp3{dollar}H) -morphine without altering the affinity constant (K{dollar}\sb{lcub}\rm d{rcub}{dollar}) in rat cortical membranes. A significant linear correlation between in vivo EEG spectral power increases and in vitro receptor binding was found. These data suggest that the regulatory effects of dynorphin A-(1-13) on morphine-induced responses are non-competitive in nature. The linear correlation between in vivo and in vitro data suggests that the antagonism by dynorphin A-(1-13) on morphine-induced EEG changes may occur at the receptor level in naive rats. In morphine-tolerant rats, dynorphin A-(1-13) i.c.v. pretreatment produced opposite effects to those found in naive rats. Instead of antagonizing morphine-induced EEG spectral power, dynorphin A-(1-13) pretreatment significantly increased cumulative i.v. morphine-induced EEG spectral power and the maximal response. The effects of dynorphin A-(1-13) on ({dollar}\sp3{dollar}H) -morphine binding were complex in cortical membrane preparations from morphine-tolerant rats. While dynorphin A-(1-13) inhibited ({dollar}\sp3{dollar}H) -morphine binding at lower morphine concentrations, it was unable to inhibit ({dollar}\sp3{dollar}H) -morphine binding at higher morphine concentrations. Significant logarithmic correlations between in vivo EEG spectral power increases and in vitro receptor binding data were found. These findings suggest that while dynorphin A-(1-13) behaved as a non-competitive antagonist in naive rats, there may be positive cooperativity between morphine and dynorphin A-(1-13) at relatively lower affinity morphine binding sites in morphine-tolerant rats. Dynorphin A-(1-13) was also found to modulate morphine-induced qualitative EEG properties differently in naive vs. morphine-tolerant rats. While dynorphin A-(1-13) pretreatment qualitatively shifted the relative distribution of cumulative i.v. morphine-induced spectral power to predominantly faster frequencies in naive rats, it had no effects on the relative distribution of EEG spectral power in morphine-tolerant rats. These data suggest that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. (Abstract shortened by UMI.)